Project Summary Alzheimer?s disease (AD) is a progressive, irreversible, age-associated neurodegenerative disease characterized by cognitive impairment, loss of memory and other mental functions. Since no current treatments for AD have been successful, the identification of therapeutic strategies that prevent or postpone decline associated with AD has become an urgent goal of biomedical science research. We will evaluate how a genetic manipulation that preserves metabolic homeostasis and extends longevity, affects the age-associated physiological decline and pathology associated with AD. Indy (I'm not dead yet) encodes a plasma membrane citrate transporter predominantly expressed in fly metabolic tissues, but it is also expressed in other tissues including the brain. We have shown that organism-wide reduction in Indy activity extends fly health and longevity by altering energy metabolism. Indy flies have decreased lipid and glucose levels, increased insulin sensitivity, increased mitochondrial biogenesis and reduced oxidative damage, among other effects. Our currently funded RO1 examines how tissue-specific INDY reduction regulates citrate levels leading to metabolic changes that preserve tissue homeostasis and slows aging non-autonomously. Here we will expand those studies to examine the effect of brain-specific Indy reduction on physiology and longevity in a fly model of AD. We will use a fly model of human AD overexpressing the amyloid precursor protein Swedish (APPswe) mutation. This mutation is linked to early-onset AD found in a Swedish pedigree caused by a detrimental APP mutation that enhances b-amyloid (A?) production. APPswe overexpression in adult flies results in neuronal cell death due to A? accumulation. This is consistent with the observed extracellular plaques in human AD caused by APPswe mutation. Ab accumulation plays a key role in oxidative damage, altered metabolism and increases risk of AD. Therefore, our working hypothesis is that a reduction of Indy will ameliorate negative effects of APPswe on metabolism, mitochondrial function and physiological decline, leading to longer life. We propose to determine effects of Indy reduction on metabolism, mitochondrial function and survivorship of male and female flies overexpressing human APPswe early and later in life (Aim 1). We will determine the mechanism of underlying metabolic and mitochondrial impairments associated with overexpressing APPswe mutation by determination of the transcriptomic profile in fly heads, and examine how these changes are modified by Indy reduction (Aim 2). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying pathology associated with AD and establish a new genetic model to study the role of Indy reduction in delaying metabolic and physiological impairments associated with AD.